Aqueous 6- 3-(3,4-dimethoxybenzyl)-amino-2-hydroxypropoxy! carbostyril composition

ABSTRACT

PCT No. PCT/JP94/01222 Sec. 371 Date Mar. 28, 1995 Sec. 102(e) Date Mar. 28, 1995 PCT Filed Jul. 25, 1994 PCT Pub. No. WO95/03802 PCT Pub. Date Feb. 9, 1995This invention provides an aqueous composition wherein a hardly water-soluble active compound, 6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy]carbostyril or a salt thereof is dissolved in water in an effective amount, particularly in an amount sufficient for exhibiting the pharmacological activities, by using as a solubilizer DL-lactic acid.

TECHNICAL FIELD

This invention relates to an aqueous composition containing a weaklybasic compound which is hardly soluble in water and is useful as amedicament, etc. More particularly, it relates to an aqueous compositioncomprising as an active ingredient 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof and as a solubilizer DL-lactic acid.

BACKGROUND ART

It is known that the 6- 3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a salt thereof used as an activeingredient in this invention has positive inotropic activity and isuseful as a myocardial contract increasing agent, specificallycardiotonics for the treatment of heart diseases such as congestiveheart failure, etc. (cf. U.S. Pat. No. 5,053,514 issued on Oct. 1,1991), and further that they are also useful as an antihistamines (cf.JP-56-008319) and as an agent for the treatment of thrombosis and aphosphodiesterase inhibitor in view of the excellent plateletaggregation inhibitory activity, phosphodiesterase inhibitory activity,cerebral blood flow increasing activity and platelet aggregatedissociation activity (cf. EP 0 531 548 A1 published on Mar. 17, 1993).

The above active compound is a weakly basic compound which is hardlysoluble in water, and hence, it is difficult to prepare an aqueouscomposition containing said compound. In order to dissolve such a weaklybasic compound in water, it is usually dissociated and dissolved bykeeping the aqueous mixture at an acidic pH range by incorporating anacidic compound into the aqueous mixture.

For example, it is disclosed in JP-55-031028 (published on Mar. 5, 1980)that a parenteral injection composition containing 1-1-{3-(4-fluorobenzoyl)propyl}-4-piperidyl!-2,3-dihydrobenzimidazole-2-thionuseful as a drug for treating psychosis and neuropathy is prepared byusing lactic acid-sodium lactate buffer solution. In this patent, it isalso disclosed that when buffer solutions containing other organic acidssuch as acetic acid, tartaric acid, citric acid, etc. are used, theactive compound precipitates, but when lactate buffer is used, noprecipitate appears.

Klaus Grohe et al. U.S. Pat. No. 4,705,789 (issued on Nov. 10, 1987)disclose readily-to-use injection and/or infusion solutions of lacticacid salts of piperazinyl-quinolone- andpiperazinyl-azaquinolone-carboxylic acids, wherein it is mentioned thatthe solutions can be stored if, besides the lactic acid salt of at leastone of the active substances and, if appropriate, customary auxiliaries,they additionally contain at least one acid which does not lead toprecipitates, in particular lactic acid. However, the lactic acid is notspecified as to its optical activity.

According to the study by the present inventors, the active compound 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril of thisinvention forms readily a hardly soluble salt with an acidic compound tobe incorporated in order to keep at an acidic pH range, and hence, it isdifficult to prepare an aqueous solution having a sufficientconcentration of the active compound effective for exhibiting thedesired pharmacological activities. Thus, it is difficult to formulatean injection or oral administrative preparation containing said activecompound, and hence, the dosage form useful as a medicament is verylimited.

DISCLOSURE OF THE INVENTION

The present inventors have further intensively studied as to thephysical properties and solubility of the active compound and its saltsof this invention and have surprisingly found that the active compoundand its salts form a salt having less water-solubility with an opticallyactive L-lactic acid and other various acids but do not form such a lesswater-soluble salt with an optically inactive DL-lactic acid and furtherthat the active compound and its salts show remarkedly improvedsolubility in water in the coexistence of DL-lactic acid.

An object of the invention is to provide an aqueous compositioncomprising as an active ingredient an effective amount of 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof and as a solubilizer DL-lactic acid and optionally conventionaladditives. Another object of the invention is to provide an aqueouscomposition containing the active 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or apharmaceutically acceptable salt thereof in a sufficient concentrationeffective as a medicament. These and other objects and advantages ofthis invention will be apparent from the following description.

BEST MODE FOR CARRYING OUT THE INVENTION

The aqueous composition of this invention comprises the above activecompound 6- 3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril ora salt thereof and DL-lactic acid in water. The salt of the activecompound includes any conventional salt with an acid, preferably with apharmaceutically acceptable organic or inorganic acid, for example,salts with organic acids (e.g. succinic acid, tartaric acid,methanesulfonic acid, or maleic acid), and salts with inorganic acids(e.g. hydrochloric acid, or sulfuric acid).

The amount of the active 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof to be contained in the aqueous composition is dependent on thedesired utilities. For the purpose of using as a medicament, the aqueouscomposition shall contain the active compound in an amount sufficientfor exhibiting the desired therapeutic effects, usually in the range ofabout 0.01 to 70% by weight based on the whole weight of thecomposition. The amount of DL-lactic acid to be incorporated as asolubilizer is not limited to any specific one but is sufficient whenthe active compound is well dissolved in the desired amount. Usually,DL-lactic acid is used in an amount of about 1 to 2000 parts by weightto 100 parts by weight of the active 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof, preferably 10 to 200 parts by weight, more preferably 20 to 80parts by weight, particularly preferably 30 to 60 parts by weight, to100 parts by weight of the active compound or a salt thereof. When theamount of DL-lactic acid is less than 10 parts by weight to 100 parts byweight of the active compound or a salt thereof, the desiredsolubilizing effect is not obtained, but on the other hand, when theDL-lactic acid is used in too much amount, the aqueous composition tendsto become disadvantageously irritative. The aqueous composition of thisinvention is usually in a pH range of about 1.0 to 8.0, preferably about2.0 to 7.0.

The active 6- 3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyrilto be contained in the aqueous composition is the most preferably a freebase, but may be a salt thereof, preferably bisuccinate and bitartrate.

The aqueous composition of this invention may optionally be incorporatedby conventional additives, such as buffering agents, antioxidants,preservatives, isotonizing agents, pH adjustors, and the like. Thebuffering agents include, for example, sodium phosphate, sodium hydrogenphosphate, potassium hydrogen phosphate, boric acid, sodium borate,citric acid, sodium citrate, tartaric acid, sodium tartrate, aceticacid, sodium acetate, epsilon-aminocaproic acid, sodium glutamate, andthe like. The antioxidants include, for example, sodium sulfite, sodiumpyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid, andthe like. The preservatives include, for example, chlorobutanol,benzalkonium chloride, benzethonium chloride, phenylmercuric salts,thimerosal, phenethyl alcohol, methylparaben, propylparaben, and thelike. The isotonizing agents are preferably nonelectrolytic substancesand include, for example, saccharoses such as glucose, sorbitol,mannitol, fructose, xylitol, and dextrose; polyhydric alcohols such asglycerin; and the like, preferably non-reducing sugars such asD-mannitol and D-sorbitol. The pH adjustors include, for example, sodiumhydroxide, hydrochloric acid, and the like. The aqueous composition ofthis invention may also be incorporated with a solubilizing auxiliarytogether with DL-lactic acid. The solubilizing auxiliary includes, forexample, polyoxyethylene glycol ethers (e.g. polyoxyethylene laurylether, polyoxyethylene oleyl ether, etc.), polyethylene glycol higherfatty acid esters (e.g. polyethylene glycol monolaurate, polyethyleneglycol monooleate, etc.), polyoxyethylene sorbitan monolaurate,polyoxyethylene fatty acid esters, and the like.

The aqueous composition of this invention is preferably used for thepreparation of various pharmaceutical preparations, such as injections,eyedrops, preparations for administering via mucous membranes,preparations suitable for oral administration, and the like. For thesepharmaceutical preparations, there may optionally be incorporated otherconventional pharmaceutically acceptable carriers or diluents, such asstabilizers, thickening agents, semi-solid base, solid base, excipients,disintegrators, flavors, and the like, in addition to theabove-mentioned buffering agents, antioxidants, preservatives,isotonizing agents and pH adjustors.

EXAMPLES

The aqueous composition of this invention is illustrated by thefollowing Example and Preparations, but should not be construed to belimited thereto.

Example 1

The active compound of this invention: 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril (100 parts byweight) and DL-lactic acid (30 parts by weight) were dissolved in water,and the solubility of the active compound was determined at 20° C. As aresult, the active compound showed a solubility of more than 70 w/v % asshown in the following Table 1. In comparison purpose, the solubilitiesof the active compound and its various salts without DL-lactic acid arealso shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                         Solubility at 20° C.                                  Active compound* +                                                                             (w/v%)       pH                                              DL-lactic acid   More than 70 N.D.                                            ______________________________________                                        Active compound  0.012        7.6                                             Hydrochloride of the                                                                           0.26         4.6                                             active compound                                                               Sulfate of the active                                                                          0.31         5.6                                             compound                                                                      Hydrobromide of the                                                                            0.32         5.3                                             active compound                                                               Monocitrate of the                                                                             0.30         4.2                                             active compound                                                               Bimalonate of the                                                                              0.34         4.4                                             active compound                                                               Bisuccinate of the                                                                             0.84         4.9                                             active compound                                                               Succinate of the 0.16         6.1                                             active compound                                                               Maleate of the active                                                                          0.19         4.5                                             compound                                                                      Bitartrate of the                                                                              0.63         3.7                                             active compound                                                               Tartrate of the active                                                                         0.27         6.7                                             compound                                                                      Methanesulfonate of the                                                                        0.12         6.7                                             active compound                                                               Bifumarate of the                                                                              0.15         3.7                                             active compound                                                               L-Lactate of the active                                                                        0.34         6.0                                             compound                                                                      ______________________________________                                         *)The active compound =                                                       6 3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril (hereinafter,     the same)                                                                

    ______________________________________                                        Preparation 1                                                                 Components            Amount                                                  ______________________________________                                        The active compound   1.0    g                                                DL-Lactic acid        0.4    g                                                D-Mannitol            4.0    g                                                Sodium hydroxide      q.s.                                                    Water for injection   q.s.                                                    Totally               100    ml                                               ______________________________________                                    

The above components are dissolved in the water for injection andfiltered with 0.2 μm membrane filter, and then filled in ampoules orvials, which are sealed and sterilized by heating with steam at 121° C.for 20 minutes to give injection preparation.

    ______________________________________                                        Preparation 2                                                                 Components             Amount                                                 ______________________________________                                        The active compound    1.0    g                                               DL-Lactic acid         0.4    g                                               Glycerin               2.0    g                                               Benzalkonium chloride  0.01   g                                               Sodium hydroxide       q.s.                                                   Sterilized purified water                                                                            q.s.                                                   Totally                100    ml                                              ______________________________________                                    

The above components are dissolved in the sterilized purified water andfiltered with 0.2 μm membrane filter, and then filled in a vessel foreyedrop, which is sealed to give eyedrops.

    ______________________________________                                        Preparation 3                                                                 Components             Amount                                                 ______________________________________                                        The active compound    1.0    g                                               DL-Lactic acid         0.1    g                                               Polyethylene glycol 400                                                                              20.0   g                                               Polyethylene glycol 1540                                                                             33.0   g                                               Polyethylene glycol 6000                                                                             37.0   g                                               Purified water         q.s.                                                   Totally                100    g                                               ______________________________________                                    

The active compound of this invention is dissolved in water containingDL-lactic acid. The solution is added polyethylene glycol bases, and themixture is stirred well until it becomes homogeneous, and then filled ina container, which is cooled to form a suppository.

    ______________________________________                                        Preparation 4                                                                 Components             Amount                                                 ______________________________________                                        The active compound    20.0   g                                               DL-Lactic acid         6.0    g                                               Simple syrup           8.0    g                                               Orange essence         0.1    g                                               Purified water         q.s                                                    Totally                100    ml                                              ______________________________________                                    

The above components are dissolved to give syrups.

    ______________________________________                                        Preparation 5                                                                 Components            Amount                                                  ______________________________________                                        The active compound   2.0    g                                                DL-Lactic acid        1.2    g                                                D-Mannitol            3.0    g                                                Sodium hydroxide      q.s.                                                    Water for injection   q.s.                                                    Totally               100    ml                                               ______________________________________                                    

By using the above components, an injection preparation is prepared inthe same manner as described in Preparation 1.

    ______________________________________                                        Preparation 6                                                                 Components              Amount                                                ______________________________________                                        Succinate of the active compound                                                                      1.0    g                                              DL-Lactic acid          0.4    g                                              D-Sorbitol              4.0                                                   Sodium hydroxide        q.s.                                                  Water for injection     q.s.                                                  Totally                 100    ml                                             ______________________________________                                    

By using the above components, an injection preparation is prepared inthe same manner as described in Preparation 1.

    ______________________________________                                        Preparation 7                                                                 Components               Amount                                               ______________________________________                                        The active compound      0.1    g                                             DL-Lactic acid           0.03   g                                             Glycerin                 1.5    g                                             Benzalkonium chloride    0.01   g                                             Sodium dihydrogen phosphate                                                                            0.04   g                                             Disodium monohydrogen phosphate                                                                        0.01   g                                             Sterilized purified water                                                                              q.s.                                                 Totally                  100    ml                                            ______________________________________                                    

By using the above components, eyedrops are prepared in the same manneras descrbined in Preparation 7.

We claim:
 1. An aqueous pharmaceutical composition which comprises:(1)as an active ingredient, 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof, (2) as a solubilizer, DL-lactic acid, and optionally (3) atleast one pharmaceutically acceptable additive, wherein the 6-3-(3,4-dimethoxy-benzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof is present in an amount of 0.01 to 70% by weight based on thetotal weight of the composition, and the DL-lactic acid is present in anamount of 1 to 2000 parts by weight per 100 parts by weight of the 6-3-(3,4-dimethoxybenzyl)-amino-2-hydroxypropoxy!carbostyril or a saltthereof.
 2. The aqueous pharmaceutical composition according to claim 1,wherein the amount of the DL-lactic acid is in the range of 10 to 200parts by weight to 100 parts by weight of the 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof.
 3. The aqueous pharmaceutical composition according to claim 1,wherein the amount of the DL-lactic acid is in the range of 20 to 80parts by weight to 100 parts by weight of the 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof.
 4. The aqueous pharmaceutical composition according to claim 1,wherein the amount of the DL-lactic acid is in the range of 30 to 60parts by weight to 100 parts by weight of the 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril or a saltthereof.
 5. The aqueous pharmaceutical composition according to claim 4,wherein said composition has a pH value of 2 of
 7. 6. The aqueouspharmaceutical composition according to claim 1, wherein the salt is abisuccinate salt or a bitartrate salt.
 7. The aqueous pharmaceuticalcomposition according to claim 1, wherein the pharmaceuticallyacceptable additive is selected from the group consisting of a bufferingagent, an antioxidant, a preservative, an isotonizing agent, and a pHadjustor.
 8. The aqueous pharmaceutical composition according to claim7, wherein the isotonizing agent is D-sorbitol or D-mannitol.